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`Brain Repair Is Possible'

November 17, 1991

Science & Technology

`BRAIN REPAIR IS POSSIBLE'

For years, Faye Day had been slipping into the nightmare of Parkinson's disease. The degenerative brain affliction, which causes difficulty in controlling movement, forced Day to leave her secretarial job three years ago. By early this year, "I was staggering and falling several times a day," recalls the 64-year-old resident of Valhermoso Springs, Ala. But in July, researchers at the University of Colorado injected brain cells from an aborted fetus into a dozen areas of Day's brain. Within weeks, the scientists believe, the new cells began churning out dopamine, a key brain chemical that is missing as a result of the disease. Now, she walks with little fear of falling. "Even if the treatment doesn't help any more than it has, it has been worth it," she says.

Day's encouraging progress presages a new era in medicine, when doctors can tackle some of the most intractable diseases of the brain, from the tremors of Parkinson's to the living death of Alzheimer's. The fetal cell transplants that Day received are just the beginning. But experiments with fetal tissue have been caught up in the politics of abortion, and the White House has banned federal funding for such work. That's one reason scientists are trying more exotic but less controversial approaches, including cell cultures and gene therapy. "We've seen extraordinary progress in the lab," says John R. Sladek, director of the Neuroscience Institute at the Chicago Medical School.

In fact, researchers plan to report an array of significant advances at the Society for Neuroscience meeting in New Orleans beginning on Nov. 10. Scientists will describe new methods for growing large amounts of fetal brain cells in the lab. They will also show how genetically altered cells, and genes themselves, can be injected into brains to combat or reverse damage caused by degenerative diseases. "We are showing that brain repair is possible," says Harvard medical school neuroscientist Ole Isacson.

NO DRUGS. These new approaches -- whether transplanting fetal brain cells or inserting a gene -- rely on the same basic strategy. They use living tissue, instead of drugs, to supply chemicals crucial to the functioning of brain cells impaired by disease. In Parkinson's, neurons that make a substance called dopamine start to degenerate. Without dopamine, scientists think, other brain cells are damaged, producing progressive loss of function. The obvious defense is to supply the missing dopamine. But drugs eventually fail because too many neurons that process dopamine are lost as the disease progresses. Hence the allure of fetal tissue. Scientists believe embryonic brain cells can grow to replace damaged dopamine-producing neurons and those harmed by lack of the substance.

So far, researchers around the world have injected fetal cells into scores of Parkinson's patients such as Faye Day. But no patient has yet come close to full recovery, and many major unknowns remain, such as how long the implanted cells will survive or whether they will be rejected. "Even if the procedure is successful in the short term, we don't know if the effect will wear off," says Dr. D. Eugene Redmond Jr. at Yale University.

As a result, some scientists argue that such tissue transplants are only a stopgap until more sophisticated alternatives can work. Physicians may one day be able to insert genetically engineered cells that produce precise amounts of dopamine or substances that may prevent a patient's own cells from dying. At the University of California at San Diego, neuroscientist Fred H. Gage used such gene-splicing and transplants to restore the ability of rats to learn and remember. He identified aged rats with memory losses. Into some of the rats he implanted cells that were engineered to make the chemical, nerve growth factor. He wanted to see if the chemical could reverse the natural degeneration of neurons. It worked, enabling the treated rats to remember how to negotiate a simple water maze.

While it may be a half dozen years before Gage's techniques can begin to tackle human scourges such as Parkinson's and Alzheimer's, other scientists are trying for speedier payoffs. Dr. Patrick Aebischer of Brown University has developed a way to encapsulate small clumps of cells that produce the desired chemicals. Holes in the plastic capsule are large enough to let substances such as dopamine pass out, but too small for antibodies to get in. That way the body's immune systems can't reject the cells when the capsule is implanted.

Aebischer has used the technique to reverse memory impairment and Parkinson-like damage in rats. And he has helped start a Providence company, Cellular Transplants Inc., that plans to apply next year for U. S. Food & Drug Administration approval to begin testing encapsulated cells in people.

Eventually, scientists hope to achieve what Harvard's Isacson calls the "science fiction scenario" -- inserting genes directly into the brain. Researchers such as Harvard neurologist Xandra O. Breakefield have already put new genes in rat brains by linking the new DNA to a weakened herpes virus. That way, the virus splices in the new genes when it infects neurons. There are still serious questions about the safety of the technique and whether the genes can be turned on long enough to do their work. But if the problems are solved, "the number of potential uses is almost overwhelming," she says. Someday genes might combat pain, degenerative diseases, epilepsy, and even depression.

FALSE HOPE? Still, scientists remain wary of dramatic claims. Neuroscientist Ignacio Madrazo of Mexico City's Center of Medicine promises to reveal at the New Orleans meeting that he transplanted fetal brain cells to treat a 37-year-old woman suffering from an advanced case of Huntington's disease, a fatal, inherited dementia that strikes in middle age. Now, "she can take better care of herself," says Madrazo. But other neuroscientists haven't duplicated Madrazo's headline-grabbing 1987 announcement that he had signficantly improved the functioning of Parkinson's patients with transplants of adrenal cells. So "these new results have to be viewed with extreme caution," says Harvard's Isacson.

Researchers don't want to raise the expectations of patients too soon. At the University of Illinois medical school, neurobiologist Jacqueline Sagen and co-workers have greatly reduced the pain suffered by three terminal cancer patients by implanting painkiller-producing adrenal cells in their spinal columns. If the results are overblown, Sagen worries, "we'll get heart-rending letters from people all over the country -- and we can't do anything for them now." Yet she and others expect that before long, these neuroscience advances will begin to make a dramatic difference.John Carey in Washington, with Stephen Baker in Mexico City